Application of CDX-MDM in Pre-Clinical Model of Murine Pulmonary Emphysema

CDX-MDM在小鼠肺气肿临床前模型中的应用

基本信息

批准号：
8524532
负责人：
MIKELL PAIGE
金额：
$ 9.97万
依托单位：
COVENANT THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-06 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8524532
关键词：
Advair Agreement Aminopeptidase Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Applications Grants Basic Science Biological Assay Biological Markers Chronic Cigarette smoke-induced emphysema Clinical Development Digestion Disease Dose Elastases Enzymes Epoxide hydrolase Future Glycine Harvest Histology Human Incubated Inflammatory Kinetics Lead Legal patent Length Leucine Leukotriene A4 Leukotriene B4 Licensing Lung Lung diseases Marketing Measures Mediation Medical Modeling Mus Nose Oral Oral Administration Pathway interactions Patients Peptides Peritoneal Pharmaceutical Preparations Pharmacologic Substance Phase Physiology Placebos Plasma Pre-Clinical Model Prevalence Process Proline Pulmonary Emphysema Randomized Sampling Severities Small Business Technology Transfer Research Staging Testing Therapeutic Therapeutic Effect Time Toxic effect Tracer Translating Treatment Efficacy Universities Ventilator Virginia Water Work absorption base cigarette smoke-induced cigarette smoking clinical application drinking water efficacy testing human disease in vivo leukotriene A4 hydrolase lung volume novel novel therapeutics peripheral blood prolyl-glycyl-proline prolyl-prolyl-glycine public health relevance tiotropium tool water solubility

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to exploit a newly discovered anti-inflammatory function involving the aminopeptidase activity of the leukotriene A4 hydrolase for the treatment of pulmonary emphysema. The leukotriene A4 hydrolase is a dual-functioning enzyme with dichotomously opposing functions. As an epoxide hydrolase, it catalyzes the conversion of leukotriene A4 to leukotriene B4 in pro-inflammatory processes. As an aminopeptidase, it catalyzes the digestion of the tripeptide sequences like Pro-Gly-Pro in anti-inflammatory processes. For the first time, we have created a pharmacological agent (4-MDM) with which the aminopeptidase activity of the leukotriene A4 hydrolase can be selectively up-regulated. We hypothesized that the treatment with 4-MDM will protect lungs from developing pulmonary emphysema. Preliminary results demonstrated that the 4-MDM treatment effectively protected murine lungs from emphysema induced by intra- nasal elastase. Subsequently, we formulated 4-MDM to be stably water soluble as a potential oral agent (CDX- MDM). Enhanced water solubility of the CDX-MDM has enabled us to administer this agent in a chronic animal model of pulmonary emphysema. Building upon this preliminary work, we propose to conduct the efficacy study of the CDX-MDM in a murine model of pulmonary emphysema induced by cigarettes smoke which resembles human disease most closely. Emphysema develops over a long duration of trigger (cigarette smoke) exposure. Therefore, developing a biomarker assay which measures the pharmaceutical effects of the drug could also be a desirable tool to overcome the long duration of onset during the development of a pharmaceutical agent. We developed a biomarker assay which the aminopeptidase activity of the leukotriene A4 hydrolase can be measured in plasma ex vivo. In this grant application, we also propose to test this assay with the plasma samples from the animals treated with the CDX-MDM or placebo. In combination, this project will provide necessary evidence on which the CDX-MDM will be developed as a potential therapy for emphysema.

描述（由申请人提供）：本提案的目的是利用新发现的涉及白三烯A4水解酶氨肽酶活性的抗炎功能来治疗肺气肿。白三烯 A4 水解酶是一种具有二分相反功能的双功能酶。作为一种环氧化物水解酶，它在促炎过程中催化白三烯 A4 转化为白三烯 B4。作为一种氨肽酶，它在抗炎过程中催化 Pro-Gly-Pro 等三肽序列的消化。我们首次创造了一种药理剂 (4-MDM)，可以选择性上调白三烯 A4 水解酶的氨肽酶活性。我们假设 4-MDM 治疗将保护肺部免于发生肺气肿。初步结果表明，4-MDM 治疗有效保护小鼠肺部免受鼻内弹性蛋白酶诱导的肺气肿的影响。随后，我们配制了稳定水溶性的 4-MDM 作为潜在的口服制剂 (CDX-MDM)。 CDX-MDM 水溶性增强，使我们能够在慢性肺气肿动物模型中使用该药物。在这项初步工作的基础上，我们建议在由香烟烟雾引起的肺气肿小鼠模型中进行 CDX-MDM 的功效研究，这种肺气肿与人类疾病最相似。肺气肿是在长期暴露于触发因素（香烟烟雾）的情况下形成的。因此，开发一种测量药物药效的生物标志物测定方法也可能是克服药物开发过程中起效时间长的问题的理想工具。我们开发了一种生物标志物测定法，可以在离体血浆中测量白三烯 A4 水解酶的氨肽酶活性。在此拨款申请中，我们还建议使用来自接受 CDX-MDM 或安慰剂治疗的动物的血浆样本来测试该测定。总而言之，该项目将为将 CDX-MDM 开发为肺气肿的潜在疗法提供必要的证据。